Novel Aromatic Compounds and Their Use in Medical Applications

ABSTRACT

Pharmaceutical compositions comprising at least one compound of the formulas (Ia) or (Ib) and a pharmaceutically acceptable carrier 
     
       
         
         
             
             
         
       
     
     wherein the symbols have the following meaning
 
—X— is e.g.
 
     
       
         
         
             
             
         
       
         
         
           
             and Y being e.g. 
           
         
       
    
     
       
         
         
             
             
         
       
     
     or the pharmaceutically acceptable salts can be applied to modulate the in-vitro and in-vivo binding processes mediated by E-, P- or L-selectin binding.

The present invention relates to compounds, compositions and methods formodulating the in vitro and in vivo processes mediated by cell adhesionmolecules. The disclosed small molecules comprise trimethoxy phenylsubunits and modulate cell adhesion molecule-mediated functionspotently.

Cell-adhesion molecule-mediated functions are part of a complex cascadeleading to the migration of circulating white blood cells (leukocytes)from the blood stream into the surrounding tissue (transmigration).Physiologically, leukocyte transmigration is of critical importance forhomeostasis and immuno-surveillance of living beings including humans.Lymphocytes for example, are constitutively leaving the blood streaminto lymphatic tissues in order to patrol for harmful antigens. Underpathological circumstances however, e.g. local or systemic inflammationand/or injury of the vascular system, this fundamental process isdys-regulated, at least in part, due to an increased surface expressionof E- and P-selectin. Consequently, the excessive leukocytetransmigration leads to a pathological cellular infiltrate withsubsequent tissue damage in several clinically relevant settings.Disease states such as Acute Lung Injury (ALI), Acute RespiratoryDistress Syndrome (ARDS), Asthma bronchiale (asthma), ChronicObstructive Pulmonary Disease (COPD), Psoriasis, Rheumatoid Arthritis,and Sepsis are all associated with tissue inflammation induced andperpetuated by pathologically activated leukocytes infiltrating therespective tissue. In addition, exaggerated leukocyte infiltrationcontributes to the pathogenesis of Ischemic-Reperfusion Injury (IRI)associated with organ transplantation, cardiopulmonary bypass orpercutaneous transluminal angioplasty.

To transmigrate, leukocytes must bind to the wall of the vascularendothelium to diffuse through the cell wall of the capillary into thesurrounding tissue. Therefore, leukocytes have to roll onto and thenadhere to the endothelial cell wall (initial rolling or “tethering”).This primary event in transmigration is mediated by the selectin familyof cell-adhesion molecules. In addition to directly binding to theendothelium, leukocytes can adhere to other leukocytes,leukocyte-particles, platelets or platelet-derived particles that arealready attached to the endothelium.

The selectin family of adhesion molecules is comprised of threestructurally related calcium-dependent carbohydrate binding cell surfaceproteins, E-, P- and L-selectin. E-selectin is expressed only oninflamed endothelium, P-selectin is expressed on inflamed endothelium aswell as on platelets and L-selectin is expressed on leukocytes.Selectins are composed of an amino terminal lectin domain, an epidermalgrowth factor (EGF)-like domain, a variable number of complementreceptor-related repeats, a hydrophobic transmembrane domain and aC-terminal cytoplasmic domain. The binding interactions leading to theadhesion of the leukocytes are supposed to be mediated by contact of thelectin domain of the selectins and various carbohydrate ligands on thesurface of the leukocytes. All three selectins can bind with lowaffinity to the carbohydrate sialyl Lewis^(x) (sLe^(x)), a glycosylmoiety present on the surface of most leukocytes. A structurally relatedglycosyl moiety, sialyl Lewis^(a) (sLe^(a)), is predominantly found onthe surface of cancer cells [K. Okazaki et al., J. Surg. Res., 1998,78(1). 78-84; R. P. McEver et al., Glycoconjugate Journal, 1997, 14(5),585-591]. In case of P-selectin, a distinct high affinity glycoproteinligand has been described [R. P. McEver, R. D. Cummings, J. Clin.Invest., 1997, 100, 485-492], the so-called P-selectin glycoproteinligand-1 (PSGL-1), which contributes to a high affinity selectin bindingby its sLe^(x) moiety as well as by parts of its peptide components, inparticular sulphated tyrosine residues [R. P. McEver, Ernst ScheringRes. Found. Workshop, 2004, 44, 137-147]. PSGL-1 is one of the mostimportant selectin ligands binding with highest affinity to P-selectin,but it also binds to E- and L-selectin [G. Constantin; Drug NewsPerspect; 2004; 17(9); 579-586]. It is a homodimeric sialomucinpredominantly expressed on leukocytes.

In inflammatory diseases, dys-regulated transmigration is, at least inpart, mediated due to an increased cell surface expression of E- andP-selectin. In contrast to their low basal expression, E- and P-selectinexpression is upregulated during inflammation, leading to a substantialrecruitment of leukocytes into the inflamed tissue. Althoughselectin-mediated cell adhesion is required for fighting infection,there are various situations in which such cell adhesion is undesirableor excessive, resulting in severe tissue damage instead of repair. Inthe case of many acute as well as chronic inflammatory disorders [e.g.,asthma, chronic obstructive pulmonary disease (COPD), psoriasis, etc.],an association between infiltration of activated leukocytes into thetissue simultaneously with a marked elevation of tissue expression ofcorresponding adhesion molecules, particularly E- and P-selectin, hasbeen demonstrated [Muller et al., J Pathol., 2002, 198(2), 270-275; DiStefano et al., Am. J. Respir. Crit. Care. Med., 1994, 149(3) 803-810;Terajima et al., Arch. Dermatol. Res., 1998, 290, 246-252]

Leukocyte infiltration may also play a role in inflammatory symptoms inthe course of transplant and graft rejection. Also the process of bloodclotting is further promoted by leukocyte-leukocyte andleukocyte-platelet binding, which occurs because leukocytes possess bothL-selectin and its corresponding ligand PSGL-1 and can thus interactwith themselves via PSGL-1, and they can also bind to platelets whichcarry P-selectin.

Therefore, the modulation of selectin-mediated cell adhesion and otherselectin mediated functions, e.g. leukocyte activation, offers apromising possibility to interfere with and stop the inflammationcascade at a very early step. Small molecule selectin antagonists shouldmodulate all three selectins simultaneously as pan-selectin-antagoniststo circumvent possible redundancies between the selectins [M. Sperandioet al., Vascular Disease Prevention, 2004, 1, 185-195].

Besides sLe^(x)/sLe^(a), the natural, high affinity ligand PSGL-1 isanother template structure for the design of small molecule selectinantagonists. As compared to sLe^(x)/sLe^(a), PSGL-1 shows high affinityfor all three selecting. To find and to detect novel small moleculedrugs that compete with PSGL-1 and PSGL-1-like ligands for selectinbinding is therefore a promising strategy to develop a novel class ofeffective pan-selectin antagonists for treating inflammatory disorders.Selectin antagonists may be designed using selectins as well as using aligand like PSGL-1 as a template structure, since they are intended tomodulate the binding between selectins and PSGL-1 or other ligands withsimilar binding motifs.

Novel small molecule selectin antagonists could meet certainrequirements to be drug-like and to have potential oral bioavailability.The term drug likeness is described in the literature [Lipinski; Adv.Drug Dev. Rev., 1997, 23, 3-25]. Beside other molecular properties,passively transported molecules are supposed to have on average arelative molecular weight of less than 500 in order to be drug like.According to these rules it is common to define compounds with arelative molecular weight of less 500 or closely above that as smallmolecules. Compounds with relative molecular weights above 500 areunlikely to be orally bioavailable. Also the presence of highly polarcarbohydrate moieties or a peptidic components is not in accordance withthe concept of drug likeness [H. Ulbrich et al., Trends Pharmacol. Sci.,2003, 24(12), 640-647; D. Slee et al., J. Med. Chem., 2001, 44,2094-2107]. The same accounts for the development of antibody-baseddrugs, because they are polypeptides and so oral administration is aproblem. Moreover, the desired compounds must be stable during thepassage through the gastrointestinal tract so that they can beingested/absorbed latest by the cells of the small intestines. This isnot the case for most glycosidic molecules and peptidic structures.

There have been various investigations to develop low-molecular weightcompounds with an modulatory effect on selectin mediated processes.These compounds include disalicylates and disalicylate-basedC-glycosides [WO 99/29706], benzyl amino sulfonic acids [WO 03/097658],diglycosylated 1,2-diols [WO 97/01569], substituted 5-memberedheterocycles [WO 00/33836], mannopyranosyloxy-phenyl-benzoic acids[EP0758243 B1], piperazine based compounds [U.S. Pat. No. 6,432,957B1],gallic acid derivatives of peptides [WO 2004/018502], gallic acid [C. C.M. Appeldoorn et al., Circulation 2005, 111, 106-112; EP 1481669A1], andquinic acid derivatives [N. Kaila et al., J. Med. Chem. 2005, 48,4346-4357]. However, none of these selectin-antagonizing compounds havesuccessfully passed clinical trials up to date [S. J. Romano, Treat.Respir Med 2005, 4(2), 85-94; M. P. Schön, Therapeutics and ClinicalRisk Management, 2005, 1(3), 201-208]. This is due to the fact, thatmany of these structures have been designed on the basis of the lowpotency template sLe^(X). Therefore, sLe^(X)-mimicking structures arelikely to show low potency. Other compounds show specificity againstdifferent members of the selectin family, but antagonizing only selectedselectins can be bypassed by other selectins [M. P. Schön, Therapeuticsand Clinical Risk Management, 2005, 1(3), 201-208]. In addition, most ofthe compounds developed so far have high molecular weights and oftenbear carbohydrates and/or peptides making them prone to degradation andmodification by peptidases and/or glycosidases. Carbohydrate-bearingstructures have further disadvantages such as high degree of chirality,anomericity, and low probability of transport through lipid bilayers.Similar disadvantages are known for peptide-bearing compounds. Someother compounds developed for antagonizing selectin mediated processescontain pyrogallol- and catechol-substructures. These motifs are proneto oxidation processes [Kumamoto M. et al., Biosci. Biotechnol.Biochem., 2001, 65(1), 126-132] making the pharmaceutical development ofthese compounds difficult. In addition, compounds with pyrogallolsubstructures, such as gallic acid, are known to be cytotoxic [E.Sergediene et al., FEBS Letters, 1999, 462, 392-396] and induceapoptosis [K. Satoh et al., Anticancer Research, 1997, 17, 2487-2490; N.Sakaguchi et al., Biochemical Pharmacology, 1998, 55, 1973-1981].

The leading compound in the field of selectin antagonists is bimosiamose[S. J. Romano, Treat. Respir Med 2005, 4(2), 85-94]. Presentlybimosiamose [D. Bock et al., New Drugs, 2003, D04, 28, p. 28; EP 0 840606 B1 ] is the most advanced compound in clinical studies Recentinvestigations support the hypothesis that bimosiamose can be consideredas PSGL-1 mimetic [E. Aydt, G. Wolff; Pathobiology; 2002-2003; 70;297-301]. This distinguishes bimosiamose from other selectinantagonists. It is, however, a high molecular weight compound withcarbohydrate structures. The pan-selectin antagonist bimosiamose seemsto lack oral bioavailability. Some observations indicate thatbimosiamose shows good affinity for P-selectin and a moderate affinityfor E- and L-selectin.

There is a strong medical need for novel highly potent pan-selectinantagonists which modulate selectin-mediated function, e.g. ofselectin-dependent cell adhesion, and for the development of methodsemploying such compounds to modulate conditions associated withselectin-ligand interaction. Most of the available anti-inflammatorypharmaceutical therapies, which are available on the market, comprisemostly corticosteroids or NSAIDs (non steroidal anti-inflammatory drugs)having several serious drawbacks/side effects, and target differentsteps of the inflammatory cascade. Unlike this, modulating the selectinfunction is a therapeutic concept intervening the inflammation cascadeat a very early stage. Almost all promising selectin antagonists so farfailed to become marketed drugs, mostly because of low potency and/orhigh molecular weight that causes problems in theirabsorption-distribution-metabolism-excretion (ADME) behaviour and thusin oral bioavailability required for the treatment of most inflammatorydisorders like rheumatoid arthritis, septic shock, atherosclerosis,reperfusion injury and many others.

Object of the invention is to provide novel small molecules, especiallynon-glycosylated/non-glycosidic and non-peptidic compounds, which areable to potently antagonize selectin-mediated processes and which haveless negative side effects during their application than prior artcompounds.

Unlike most of the sLe^(X)-mimicking compounds developed in this field,the inventive compounds are not prone to glycosidases or peptidases.Most of the selectin antagonists developed so far are structurally andbiologically based on the properties of sLe^(x) or sLe^(a). Theseresulting compounds showed, therefore, low biological activity liketheir template structures. This invention, however, provides novelpotent small and drug like pan-selectin antagonists that have beeninvented on the basis of biological in vitro assays mimicking PSGL-1 andPSGL-1-like ligands or any ligands bearing sLe^(x) or sLe^(a) andtyrosinesulfate motifs [N. V. Bovin; Biochem Soc Symp.;2002;(69):143-60. N. V. Bovin; Glycoconj. J; 1998; 15(5); 431-46. T. V.Pochechueva et al.; Bioorg Med Chem. Lett.; 2003; 13(10);1709-12. G.Weitz-Schmidt et al.; Anal. Biochem.; 1996; 238; 184-190].

The present invention provides pharmaceutical compositions comprising atleast one compound having the general structure of formulas (Ia) or (Ib)and a pharmaceutically acceptable carrier which is useful in medicine.

wherein the symbols and substituents have the following meaning

-   -   —X—=

-   -   with m=0,1; n=an integer from 1 to 3

-   -   wherein “ring” is

-   -   and with R¹ being H, NO₂, CF₃, F, Cl, Br, I, CN, CH₃, NH₂,        NHAlkyl, NHAryl, NHAcyl and k=0,1

-   -   T being O, S or [H,H]; p=0,1,2,

-   -   the double bond is either E- or Z-configurated

-   -   with -E- being —(CH₂—)_(q)NH— and q=0, 1, 2, 3    -   —Y=

-   -   with s being 0 or 1,    -   R² being CO₂H, CO₂Alkyl, CO₂Aryl, CO₂NH₂, CO₂Aralkyl, SO₃H,        SO₂NH₂, PO(OH)₂, 1-H-tetrazolyl-, CHO, COCH₃, CH₂OH, NH₂,        NHAlkyl, N(Alkyl)Alkyl′, OCH₃, CH₂OCH₃, SH, F, Cl, Br, I, CH₃,        CH₂CH₃, CN, CF₃    -   R³ independently from R² being H, CH₃, CH₂CH₃, CF₃, F, Cl, Br,        I, CN, NO₂ and    -   R⁴ independently from R² and R³ being H, CH₃, CH₂CH₃, CF₃, F,        Cl, Br, I, CN, NO₂, R²    -   R⁵ being H, NO₂, CF₃, F, Cl. Br, I, CN, CH₃, OCH₃, SH, NH₂    -   and —W—=—(CH₂—)_(v), cis-CH═CH— or trans-CH═CH—, and v being        0,1,2;    -   in case that —W— is cis-CH═CH— or trans-CH═CH—, R² must not be        NH₂ or SH;

-   -   R⁶ independently from R² being H, F, Cl, Me, tert-Bu, CN, NH₂

-   -   with t being 0,1,2

-   -   R⁷ independently from R² being H, NO₂, CF₃, F, Cl, Br, I, CN,        CH₃, OCH₃, SH, NH₂,

-   -   R⁸ independently from R² being H, F, Cl, Me, tert-Bu, CN, NH₂

-   -   with K=NH, NMe, O, S

-   -   or the pharmaceutically acceptable salts, esters or amides and        prodrugs of the above identified compounds of formulas (Ia) or        (Ib).

In a preferred embodiment of the invention, the compositions comprise acompound of the formulas (Ia) or (Ib) and a pharmaceutically acceptablecarrier which is useful in a medicine,

-   -   wherein the symbols, indices and substituents have the following        meaning    -   —X-=

-   -   with m=0,1; n=an integer from 1 to 3

-   -   wherein “ring” is

-   -   and with R¹ being H, NO₂, CF₃, F, Cl, Br, I, CN, CH₃, NH₂,        NHAlkyl, NHAryl, NHAcyl and k=0,1

-   -   T being O, S or [H,H]; p=0,1,2,    -   —Y=

-   -   with s being 0 or 1,    -   R² being CO₂H, CO₂Alkyl, CO₂Aryl, CO₂NH₂, CO₂Aralkyl, SO₃H,        SO₂NH₂, PO(OH)₂, 1-H-tetrazolyl-, CHO, COCH₃, CH₂OH, NH₂,        NHAlkyl, N(Alkyl)Alkyl′, OCH₃, CH₂OCH₃, SH, F, Cl, Br, I, CH₃,        CH₂CH₃, CN, CF₃    -   R³ independently from R² being H, CH₃, CH₂CH₃, CF₃, F, Cl, Br,        I, CN, NO₂ and    -   R⁴ independently from R² and R³ being H, CH₃, CH₂CH₃, CF₃, F,        Cl, Br, I, CN, NO₂, R²    -   R⁵ being H, NO₂, CF₃, F, Cl, Br, I, CN, CH₃, OCH₃, SH, NH₂    -   and —W—=—(CH₂—)_(v), cis-CH═CH— or trans-CH═CH—, and v being        0,1,2;    -   in case that —W— is cis-CH═CH— or trans-CH═CH—, R² must not be        NH₂ or SH;

-   -   with t being 0,1,2    -   -Z=

-   -   R⁷ independently from R² being H, NO₂, CF₃, F, Cl, Br, I, CN,        CH₃, OCH₃, SH, NH₂,

-   -   with K=NH, NMe, O, S    -   or the pharmaceutically acceptable salts, esters or amides and        prodrugs of the above identified compounds of formulas (Ia) or        (Ib).

Preferred pharmaceutical compositions comprise compounds of formulas(IIa) or (IIb)

-   -   wherein —Y is like defined above and wherein —X′— is X (a), X        (b), X (c), and X (d) like defined above. Preferred definitions        of —X′— are X(a), X(b) and X(c), more preferred are X(b) and        X(c).

Further preferred pharmaceutical compositions comprise compounds offormulas (Al), (B1), (A2) or (B2)

-   -   wherein —X′— and —Y are like defined above and wherein —X″— is

-   -   and wherein —Y′ is

-   -   wherein all indices, symbols and substituents are like defined        above.    -   In a further embodiment of the invention, the compounds of the        formulas A1, A2, B1 and B2 are used, wherein —X′— and —Y are as        defined as above and wherein —X″— is

-   -   and wherein —Y′ is

-   -   and wherein all other indices, symbols and substituents are as        defined above.

Particularly preferred pharmaceutical compositions comprise compounds offormulas (C) and (D)

-   -   wherein —X″— and —Y′ are like defined above.

Very particularly preferred pharmaceutical compositions comprise atleast one compound of formulas (E) and (F)

-   -   wherein —X″— is like defined above and —Y″ is

-   -   with R⁹ being CO₂H, CO₂alkyl, CO₂aryl, CO₂NH₂, CO₂aralkyl,        CH₂SO₃H, CH₂SO₂NH₂, CH₂PO(OH)₂, 1-H-tetrazolyl, CHO, COCH₃,        CH₂OH, CH₂NH₂, CH₂NHalkyl, CH₂N(alkyl)alkyl′, CH₂OCH₃, CH₂SH,        wherein the indices, symbols and substituents are defined as        above.

The invention also relates to pharmaceutical compositions, wherein thecompounds are defined by formulas (E) or (F)

-   -   wherein —X″— is as defined as above and —Y″ is

-   -   with R⁹ being CO₂H, CO₂alkyl, CO₂aryl, CO₂NH₂, CO₂aralkyl,        CH₂SO₃H, CH₂SO₂NH₂, CH₂PO(OH)₂, 1-H-tetrazolyl, CHO, COCH₃,        CH₂OH, CH₂NH₂, CH₂NHalkyl, CH₂N(alkyl)alkyl′, CH₂OCH₃, CH₂SH,    -   wherein all other indices, symbols and substituents are as        defined above.

These chemical compounds (C), (D), (E) and (F) are also new compoundsfor themselves.

All compounds as described before present the ability of modulating celladhesion and modulate selectin—as well as PSGL-1-like mediated binding.The compounds have the ability to modulate the interaction of selectinswith sLe^(x)/sLe^(a) and also the interaction between selectins andtyrosinesulfate residues. Therefore they are useful for the treatment ofacute and chronic inflammatory disorders, as well as other medicalconditions where selectin mediated processes play a role.

The term “pharmaceutical” includes also diagnostic applications.

The term “pharmaceutical” includes also prophylactic applications inorder to prevent medical conditions where selectin mediated processesplay a role.

The term “pharmaceutical” includes also applications, where compounds ofthe present invention may be used as vehicles for drug targeting ofdiagnostics or therapeutics.

The invention provides pharmaceutical compositions comprising compoundsof formulas (Ia) or (Ib) and in a preferred variant of formulas (IIa) or(IIb).

In a further preferred variant the invention provides pharmaceuticalcompositions comprising at least one compound of formula (A1), (A2),(B1) or (B2).

In a particularly preferred variant the invention providespharmaceutical compositions comprising at least one compound of formula(C) or (D).

In a very particularly preferred variant the invention providespharmaceutical compositions comprising at least one compound of formula(E) or (F).

The present invention further provides a method of modulating thebinding of P-selectin, L-selectin or E-selectin to sLe^(x) or sLe^(a)and tyrosinesulfate residues comprising the step of administering to apatient an effective amount of at least one compound having thestructure of formulas (Ia) or (Ib) to modulate the binding of P-, E- orL-selectin to sLe^(x) or sLe^(a) and tyrosinesulfate. It has been foundthat compounds having the formulas (Ia) or (Ib) shown above act tomodulate E-, P- or L-selectin binding.

As used herein the terms “alkyl” shall mean a monovalent straight chainor branched chain group of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or10 or 11 or 12 carbon atoms including, but not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.“Alkyl” is independently from each other and can be different oridentical.

The term “aryl” shall mean carbocyclic and heterocyclic aromatic groupsincluding, but not limited to, phenyl, 1-naphthyl, 2-naphthyl,fluorenyl, (1,2)-dihydronaphthyl, indenyl, indanyl, thienyl,benzothienyl, thienopyridyl and the like.

The term “aralkyl” (also called arylalkyl) shall mean an aryl groupappended to an alkyl group including, but not limited to, benzyl,1-naphthylmethyl, 2-naphthylmethyl, fluorobenzyl, chlorobenzyl,bromobenzyl, iodobenzyl, alkoxybenzyl (wherein “alkoxy” means methoxy,ethoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy an the like),hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidinobenzyl,fluorenylmethyl, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl,1-naphthylethyl and the like.

The term “acyl” shall mean —(CHO) or —(C═O)-alkyl or —(C═O)-aryl or—(C═O)-aralkyl including, but not limited to, formyl, acetyl,n-propionyl, isopropionyl, n-butyryl, isobutyryl, pivaloyl, benzoyl,4-nitrobenzoyl and the like.

The term “pharmaceutically acceptable salts, esters, amides andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with tissues of patients without unduetoxicity, irritation, allergic response and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe present invention. The term “salts” refers to the relativelynon-toxic, inorganic and organic acid addition salts of the compounds ofthe present invention. These salts can be prepared in situ during thefinal isolation and purification of the compounds or by separatelyreacting the purified compounds in its free form with a suitableinorganic or organic acid or base and isolating the salt thus formed.Representative salts of the compounds of the present invention includethe hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, palmitate, stearate, laurate, borate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate,laurylsulphonate salts and the like. These may include cations based onthe alkali and alkalineearth metals, such as sodium, lithium, potassium,calcium, magnesium and the like, as well as non-toxic ammonium,quaternary ammonium and amine cations including, but not limited to,ammonium, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

Examples of the pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁, C₂, C₃, C₄, C₅ and C₆ alkylesters wherein the alkyl group is a straight or branched chain.Acceptable esters also include C₅, C₆ and C₇ cycloalkyl esters as wellarylalkyl esters such as, but not limited to benzyl. C₁, C₂, C₃, C₄, C₅and C₆ alkyl ester are preferred. Esters of the compounds of the presentinvention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of compoundsof this invention include amides derived from ammonia, primary C₁, C₂,C₃, C₄, C₅ and C₆ alkyl amines and secondary C₁, C₂, C₃, C₄, C₅ and C₆dialkyl amines wherein the alkyl groups are straight or branched chains.In the case of secondary amines the amine may also be in the form of a 5or 6 membered heterocycle containing one nitrogen atom. Amides derivedfrom ammonia, C₁, C₂ and C₃ alkyl primary amides and C₁ to C₂ dialkylsecondary amides are preferred. Amides of the compounds of the presentinvention may be prepared according to conventional methods.

The term “prodrug” refers to one or more compounds that are rapidlytransformed in vitro and from a non-active to active state in vivo toyield the parent compound of the above formulas (Ia) or (Ib), forexample by hydrolysis in blood or in vivo metabolism.

It is also contemplated that pharmaceutically active compositions maycontain a compound of the present invention or other compounds thatmodulate or compete with E-selectin or P-selectin or L-selectin binding.

Pharmaceutically active compositions of the present invention comprise apharmaceutically acceptable carrier and a compound of formulas (Ia) or(Ib), whereby a pharmaceutically acceptable carrier can also be amedically appropriate nano-particle, dendrimer, liposome, microbubble orpolyethylene glycol (PEG). The pharmaceutical compositions of thepresent invention may include one or more of the compounds having theabove structure (Ia) or (Ib) formulated together with one or more,physiologically acceptable carriers, adjuvants or vehicles, which arecollectively referred to herein as carriers, for parenteral injection,for oral administration in solid or liquid form, for rectal or topicaladministration and the like.

The compositions can be administered to humans and animals eitherorally, rectally, parenterally (intravenously, intramuscularly,intradermaly or subcutaneously), intracistemally, intravaginally,interperitoneally, locally (powders, ointments or drops), or as a buccalor by inhalation (nebulized, or as nasal sprays).

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,stabilizers, antioxidants, preservatives (e.g. ascorbic acid, sodiumsulfite, sodium hydrogen sulfite, benzyl alcohol, EDTA), dispersions,suspensions or emulsions and sterile powders for reconstitution intosterile injectable solution or dispersion. Examples of suitable aqueousand nonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyol, (propylene glycol, polyethylene glycol, glycerol andthe like), suitable mixtures thereof, vegetable oils (such as olive orcanola oil) and injectable organic esters such as ethyl oleate. Properfluidity can be maintained, for examples, by the use of a coating suchas lecithin, by the maintenance of the required particle size in thecase of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Prevention of the actionsof microorganisms can be ensured by various antibacterial and antifungalagents, for examples, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexamples sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for examples aluminium monostearate andgelatin.

If desired, and for more effective distribution, the compounds can beincorporated into slow or timed release or targeted delivery systemssuch as polymer matrices, liposomes, and microspheres. They may besterilized, for example, by filtration through a bacteria-retainingfilter, or by incorporating sterilizing agents in the form of sterilewater, or some other sterile injectable medium immediately before use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound or a prodrug is admixed with at least one inert customaryexcipient (or carrier) such as sodium citrate or dicalcium phosphate or(i) fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol and silicic acid, (ii) binders, as for example,carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone,sucrose and acacia, (iii) humectants, as for example, glycerol, (divdisintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, aliginic acid, certain complex silicates andsodium carbonate, (v) solution retarders, as for examples, paraffin,(vi) absorption accelerators, as for example, quaternary ammoniumcompounds, (vii) wetting agents, as for examples, cetyl alcohol andglycerol monostearate, (viii) adsorbents, as for example, kaolin andbentonite, and (ix) lubricants, as for example, talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfateand mixtures thereof. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatine capsules using excipients as lactose ormilk sugars as well as high molecular polyethylene glycols and the like.Solid dosage forms such as tablets, dragées, capsules, pills andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain opacifyingagents, and can also be of such compositions that they release theactive compound or compounds in a certain part of the intestinal tractin a delayed manner. Examples of embedding compositions that can be usedare polymeric substances and waxes. The active compounds can also be inmicroencapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as water or other solvents,solubilizing agents and emulsifiers, as for example, ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, cannola oil, caster oil and sesame seed oil,glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan or mixtures of these substances, and the like.Besides such inert diluents, the compositions can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweeting, flavouring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, tragacanth or mixtures of thesesubstances and the like.

Compositions for rectal administrations are preferably suppositories,which can be prepared by mixing the compounds of the present inventionwith suitable nonirritating excipients or carriers such as cacao butter,polyethylene glycol or a suppository wax, which are solid at ordinarytemperatures but liquid at body temperature and therefore melt in therectal or vaginal cavity and release the active component. Dosage formsfor topical administration of a compound of this invention includeointments, powder, sprays and inhalants.

The active component is admixed under sterile conditions with aphysiologically acceptable carrier and any needed preservatives, buffersor propellants as may be required. Ophthalmic formulations, eyeointments, suspensions, powder and solutions are also contemplated asbeing within the scope of this invention.

The compounds of the present invention can also be incorporated into orconnected to liposomes or administrated in the form of liposomes. As isknown in the art, liposomes are generally derived from phospholipids orother lipid substances. Liposomes are formed by mono or multilamellarhydrated liquid crystals that are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable metabolized lipid capable offorming liposomes can be used. The present compositions in liposome formcan contain, in addition to the selectin binding antagonists of thepresent invention, stabilizers, preservatives, excipients and the like.The preferred lipids are the phospholipids and the phosphatidyl cholines(lecithins), both natural and synthetic. Methods to form liposomes arewell known in the art.

Non-parenteral dosage forms may also contain a bioavailability enhancingagent (e.g. enzyme modulators, antioxidants) appropriate for theprotection of the compounds against degradation. Actual dosage levels ofactive ingredient in the composition of the present invention may bevaried so as to obtain an amount of active ingredient that is effectiveto obtain the desired therapeutic response for a particular compositionand method of administration. The selected dosage level, therefore,depends on the desired therapeutic effect, on the route ofadministration, on the desired duration of treatment and other factors.The total daily dosage of the compounds on this invention administeredto a host in single or divided doses may be in the range up to 50 mg perkilogram of body weight. Dosage unit compositions may contain suchsubmultiples thereof as may be used to make up the daily dosage. It willbe understood, however, that the specific dose level for any particularpatient, whether human or other animal, will depend upon a variety offactors including the body weight, general health, sex diet, time androute of administration, rates of absorption and excretion, combinationwith other drugs and the severity of the particular disease beingtreated.

In particular, the compounds of the present invention may be used totreat a variety of diseases relating to inflammation and cell-cellrecognition and adhesion. For example, the compounds of the presentinvention may be administrated to a patient to treat Chronic ObstructivePulmonary Disease (COPD), acute lung injury (ALI), cardiopulmonarybypass, acute respiratory distress syndrome (ARDS), Crohn's disease,septic shock, sepsis, chronic inflammatory diseases such as psoriasis,atopic dermatitis, and rheumatoid arthritis, and reperfusion injury thatoccurs following heart attacks, strokes, atherosclerosis, and organtransplants, traumatic shock, multi-organ failure, autoimmune diseaseslike multiple sclerosis, percutaneous transluminal angioplasty, asthmaand inflammatory bowel disease. In each case, an effective amount of thecompounds of the present invention is administered either alone or aspart of a pharmaceutically active composition to a patient in need ofsuch treatment. It is also recognized that a combination of thecompounds may be administered to a patient in need of suchadministration. The compounds of the present invention may also beadministered to treat other diseases that are associated with cell-celladhesion. As the present compounds modulate the binding of E-selectin orP-selectin or L-selectin, any disease that is related to thisinteraction may potentially be treated by the modulation of this bindinginteraction.

In addition to being found on some white blood cells, sLe^(a) is foundon various cancer cells, including lung and colon cancer cells. It hasbeen suggested that cell adhesion involving sLe^(a) may be involved inthe metastasis of certain cancers and antagonists of sLe^(a) bindingmight be useful in treatment of some forms of cancer.

The use of the active ingredients according to the invention or ofcosmetic or topical dermatological compositions with an effectivecontent of active ingredient according to the invention surprisinglyenables effective treatment, but also prophylaxis of skin ageing causedby extrinsic and intrinsic factors.

The invention particularly relates to the use of a compound of formula(Ia) or (Ib) or a stereoisomeric form thereof for the preparation of acosmetic or dermatological composition.

The amount used of the active compound or a stereoisomeric form thereofcorresponds to the amount required to obtain the desired result usingthe cosmetic or dermatological compositions. One skilled in this art iscapable of evaluating this effective amount, which depends on thederivative used, the individual on whom it is applied, and the time ofthis application. To provide an order of magnitude, in the cosmetic ordermatological compositions according to the invention, the compound offormula (Ia) or (Ib) or a stereoisomeric form thereof may beadministered in an amount representing from 0.001% to 40% by weight,preferentially 0.005% to 30% by weight and more preferentially from0.01% to 20% by weight.

A further aspect covers cosmetic compositions comprising a compound offormula (Ia) or (Ib) or a stereoisomeric form thereof and at least onecosmetically tolerable component, e.g. a cosmetically tolerablecomponent for skin applications.

The amounts of the various components of the physiological medium of thecosmetic composition according to the invention are those generallyincluded in the fields under consideration. When the cosmeticcomposition is an emulsion, the proportion of the fatty phase may rangefrom 2% to 80% by weight and preferably from 5% to 50% by weightrelative to the total weight of the cosmetic composition.

Thus, the cosmetic composition should contain a non-toxicphysiologically acceptable medium that can be applied to human skin. Fora topical application to the skin, the cosmetic composition may be inthe form of a solution, a suspension, an emulsion or a dispersion ofmore or less fluid consistency and especially liquid or semi-liquidconsistency, obtained by dispersing a fatty phase in an aqueous phase(O/W) or, conversely, (W/O), or alternatively a gel. A cosmeticcomposition in the form of a mousse or in the form of a spray or anaerosol then comprising a pressurized propellant may also be provided.Also the compositions may be in the form of a haircare lotion, a shampooor hair conditioner, a liquid or solid soap, a treating mask, or afoaming cream or gel for cleansing the hair. They may also be in theform of hair dye or hair mascara.

The cosmetic compositions of the invention may also comprise one or moreother ingredients usually employed in the fields under consideration,selected from among formulation additives, for instance aqueous-phase oroily-phase thickeners or gelling agents, dyestuffs that are soluble inthe medium of the cosmetic composition, solid particles such as mineralor organic fillers or pigments in the form of microparticles ornanoparticles, preservatives, fragrances, hydrotopes or electrolytes,neutralizers (acidifying or basifying agents), propellants, anionic,cationic or amphoteric surfactants, polymers, in particularwater-soluble or water-dispersible anionic, nonionic, cationic oramphoteric film-forming polymers, mineral or organic salts, chelatingagents; mixtures thereof.

The cosmetic compositions may be used to inhibit the micro-inflammatorycycle. Thus, the present invention also relates to cosmetic compositionscomprising a compound of formula (Ia) or (Ib) or a stereoisomeric formthereof that is used for the cosmetic treatment or cosmetic prophylaxisof micro-inflammatory conditions.

Cosmetic compositions comprising a compound of formula (Ia) or (Ib) or astereoisomeric form thereof that is used for the cosmetic treatment orcosmetic prophylaxis of skin ageing caused by intrinsic factors are alsosubject of the present invention. Intrinsic factors responsible for skinageing are genetically programmed determinants including age, hormonalstatus, and psychological factors.

Beside cosmetically inactive ingredients the cosmetic compositions ofthe present invention may also comprise one or more cosmetically activeingredients with beneficial action on the skin. Thus, the presentinvention relates to cosmetic compositions comprising a compound offormula (Ia) or (Ib) or a stereoisomeric form thereof and at least onefurther cosmetically active ingredient, e.g. an UV-blocker or proteins.

Dermatological compositions comprising a compound of formula (Ia) or(Ib) or a stereoisomeric form thereof and at least one dermatologicallytolerable component, e.g. a dermatologically tolerable component forskin applications, are also subject of the invention.

Dermatologically tolerable components that can be used for thedermatological compositions described here are identical to thecosmetically tolerable components as defined in this invention.

A further embodiment of this invention are dermatological compositionscomprising a compound of formula (Ia) or (Ib) or a stereoisomeric formthereof that is used for the dermatological treatment, dermatologicaldiagnosis or dermatological prophylaxis of micro-inflammatoryconditions.

In particular the invention covers dermatological compositionscomprising a compound of formula (Ia) or (Ib) or a stereoisomeric formthereof that is used for the dermatological treatment, dermatologicaldiagnosis or dermatological prophylaxis of itching and skin ageingcaused by extrinsic factors. Extrinsic factors include environmentalfactors in general; more particularly photo-ageing due to exposure tothe sun, to light or to any other radiation, atmospheric pollution,wounds, infections, traumatisms, anoxia, cigarette smoke, hormonalstatus as response to external factors, neuropeptides, electromagneticfields, gravity, lifestyle (e.g. excessive consumption of alcohol),repetitive facial expressions, sleeping positions, and psychologicalstressors.

In addition to dermatologically inactive ingredients the dermatologicalcompositions may also comprise dermatologically or pharmaceuticallyactive ingredients. Thus, the present invention also relates todermatological compositions comprising a compound of formula (Ia) or(Ib) or a stereoisomeric form thereof and at least one furtherdermatologically or pharmaceutically active ingredient. Thedermatologically or pharmaceutically active ingredients that can be usedfor the dermatological compositions described herein are defined as thecosmetically active ingredients defined above. Dermatologically orpharmaceutically active ingredients can be identical to the cosmeticallyactive ingredients as defined in this invention.

Another subject of the present invention are dermatological compositionscomprising a compound of formula (Ia) or (Ib) or a stereoisomeric formthereof and at least one further dermatologically or pharmaceuticallyactive ingredient characterized in that it is used for thedermatological treatment, dermatological diagnosis or dermatologicalprophylaxis of micro-inflammatory conditions.

In particular, the present invention relates to dermatologicalcompositions comprising a compound of formula (Ia) or (Ib) or astereoisomeric form thereof and at least one further dermatologically orpharmaceutically active ingredient characterized in that it is used forthe dermatological treatment, dermatological diagnosis or dermatologicalprophylaxis of itching and skin ageing caused by extrinsic factors.

Ageing of the skin may also be caused by a combination of intrinsic andextrinsic factors. Therefore, the present invention also relates todermatological compositions comprising a compound of formula (Ia) or(Ib) or a stereoisomeric form thereof and at least one furtherpharmaceutically or cosmetically active ingredient characterized in thatit is used for the cosmetic and dermatological treatment and cosmeticand dermatological prophylaxis of skin ageing caused by a combination ofintrinsic and extrinsic factors.

Another embodiment of this invention is a process for the preparation ofa cosmetic composition by mixing a compound of formula (Ia) or (Ib) or astereoisomeric form thereof, at least one cosmetically tolerablecomponent and eventually further cosmetically active ingredients.

In particular, a process for the preparation of a cosmetic compositionby mixing a compound of formula (Ia) or (Ib) or a stereoisomeric formthereof, at least one cosmetically tolerable component and eventuallyfurther cosmetically active ingredients, wherein the compositionincludes from 0.01% to 20% by weight of compound of formula (Ia) or Ib)or a stereoisomeric form thereof, based on the total weight of thecomposition is subject of this invention.

A further aspect deals with a process for the preparation of adermatological composition by mixing a compound of formula (Ia) or (Ib)or a stereoisomeric form thereof, at least one dermatologicallytolerable component and eventually further pharmaceutically activeingredients.

Many of the compounds of the present invention may be synthesizedaccording to the following general synthetic schemes.

In SCHEME 1 an amino acid of type (1) is reacted to the correspondingmethyl ester (2) under heating with acidic methanol. Ester (2) isreacted with a trimethoxy-phenyl-alkylic acid under state-of-the-artconditions (i.e. N′-(3-dimethylaminopropyl)-N-ethyl carbodiimide (EDC),triethylamine and 4-dimethylaminopyridine (DMAP) in a chlorinatedsolvent) to the amide (3). Alternatively diisopropyl carbodiimide (DIC)and hydroxybenzotriazole (HOBt) may be used for this reaction step. Thesynthesis sequence shown in SCHEME 1 leading to compounds like (3) isnot only reduced to the Y—H building blocks like (1) but may begenerally applied to all other Y—H type building blocks leading tocompounds of type (A1), (A2), (B1) and (B2) as shown in the paragraphbefore.

In SCHEME 2 a carboxy substituted thiophene like (4) is reacted to thecorresponding ethyl ester (5) under heating in acidic ethanol. Ester (5)is brominated with N-bromosuccinimide in anhydrous chloroform andglacial acetic acid to give (6) which is further reacted with2-Amino-benzeneboronic acid under a state-of-the-art Suzukitransformation (i.e. Tetrakis(triphenylphosphine)-palladium, aqueoussodium carbonate, ethanol, toluene) to the biaryl (7). Biaryl (7) isreacted with a trimethoxy-phenyl-alkylic acid, EDC, triethylamine andDMAP in a chlorinated solvent to the amide (8). Alternatively DIC andHOBt may be used for this reaction step.

In SCHEME 3 Methyl-3-bromobenzoate (9) is reacted under inert conditionswith a Trimethoxyphenylboronic acid under Suzuki-type basic conditions(Pd(PPh₃)₄ and aqueous sodium bicarbonate in dimethoxyethane) to abiphenyl of type (10) which is further hydrolized with aqueous lithiumhydroxide in acetonitrile to give the corresponding carboxylic acid (11)which was converted to building block of type (12) by reaction withoxalyl chloride in anhydrous dichloromethane.

In SCHEME 4 an acid chloride like (12) is reacted with an aniline ofgeneral type (13) under basic conditions (triethylamine in a chlorinatedsolvent) to form the anilide (14). Alternatively pyridine may be usedfor this reaction step.

In case that R² and/or R⁴ contain carboxylic acid functionalities, thoseare protected as their corresponding methyl or ethyl esters before andhydrolized afterwards to release the carboxylic acid functionalities.The ester hydrolysis is done with LiOH in MeCN or THF/MeOH.

The synthesis sequence shown in SCHEME 4 leading to compounds like (14)is not only reduced to X—Y—H and Y—H building blocks like (13) but maybe generally applied to all other X—Y—H and Y—H type building blocksleading to compounds of type (A1), (A2), (B1) and (B2) as shown in theparagraphs before.

In SCHEME 5 the generation of building block (19) is outlined, wherebythe furane (16) is available by NBS-bromination of methyl furoate (15)and pinacolyl borane of type (18) is available by Pd-catalyzed borationof anilines like (17). Suzuki-type coupling of (16) and (18) withPd(PPh₃)₄ leads to biaryls of type (19).

In SCHEME 6 a biaryl of type (19) is reacted with atrimethoxy-phenyl-alkylic acid under state-of-the-art conditions (i.e.N′-(3-dimethylaminopropyl)-N-ethyl carbodiimide (EDC), triethylamine and4-dimethylaminopyridine (DMAP) in a chlorinated solvent) to the amide oftype (20). Alternatively diisopropyl carbodiimide (DIC) andhydroxybenzotriazole (HOBt) may be used for this reaction step. (20) isthen hydrolized to acid of type (21) whether with LiOH in MeCN orTHF/MeOH.

The present invention is furthermore illustrated by the followingrepresentative examples.

EXAMPLE 1 {3-[3-(2,3,4-Trimethoxy-phenyl)-propionylamino]-phenyl}-aceticacid methyl ester (24)

Step 1: Dissolve (3-Amino-phenyl)-acetic acid ((22), 700 mg, 4.63 mmol)in MeOH (21 mL) and add conc. sulfuric acid (0.27 mL, 5.09 mmol). Stirthe reaction mixture for 2d under reflux. Cooled mixture to roomtemperature (rt), remove solvent under reduced pressure and prepurifythe residue by flushing it over a short pad of silica gel using EtOAc.Remove solvent again and partition the residue between EtOAc andsaturated aqu. NaHCO₃ (1+1). Extracte the aqueous layer 3 times withEtOAc, washe the combined organic layers with brine and dried withNa₂SO₄. Remove solvent under reduced pressure and dry the residuewithout further purification in oil pump vacuum to obtain product (23)as a light yellow oil (708 mg, 92%). ¹H NMR (400 MHz, CDCl₃): 3.51 (s,2H); 3.67 (s, 3H); 6.57 (dd, 1H, J₁=7.8 Hz, J₂=1.8 Hz); 6.60 (br.Ψt, 1H,J=1.8 Hz); 6.65 (br.d, 1H, J≈7.8 Hz); 7.08 (Ψt, 1H, J=7.8 Hz).

Step 2: (The following reaction is done in an anhydrous N₂ atmosphere.)Dissolve EDC hydrochloride (187 mg, 0.98 mmol) and triethylamine (0.14mL, 1.00 mmol) in anhydrous dichloromethane (3.5 mL) and stir for 5 minat rt. Added 3-(2,3,4-Trimethoxy-phenyl)-propionic acid (234 mg, 0.97mmol) and DMAP (12 mg, 0.10 mmol) and stir for 10 min. Add ester (23)(107 mg, 0.65 mmol) and stir the reaction solution overnight at rt.

Hydrolize the reaction solution with saturated aqu. NH₄Cl followed bywater, separate layers, extracte aqu. layer with dichloromethane (3times) and washe the combined organic layers with water and brine anddry with Na₂SO₄. Remove solvent under reduced pressure.

Purify crude product by preparative radial chromatography (silica gel 60PF, EtOAc/CyH 1+1) to obtain product (24) as a white solid (209 mg,83%). [K. C. Nicolaou; P. S. Baran; Y.-L. Zhong; K. Sugita; J. Am. Chem.Soc.; 2002; 124; 10; 2212-2220]. ¹H NMR (400 MHz, CDCl₃): 2.62 (t, 2H,J=7.5 Hz); 2.95 (t, 2H, J=7.5 Hz); 3.58 (s, 2H); 3.67 (s, 3H); 3.82 (s,3H); 3.84 (s, 3H); 3.91 (s, 3H); 6.59 (d, 1H, J=8.6 Hz); 6.86 (d, 1H,J=8.6 Hz); 6.98 (br.d, 1H, J=7.8 Hz); 7.32 (Ψt, 1H, J=7.8 Hz); 7.38(br.d, 1H, J=7.8 Hz); 7.41 (br.s, 1H).

EXAMPLE 2(5-{2-[2-(2,3,4-Trimethoxyphenyl)-acetylamino]-phenyl}-thiophen-2-yl]aceticacid (31)

Step 1: Dissolve Thiophene-2-yl-acetic acid (25) (2.44 g, 17.1 mmol) inethanol (35 mL) and add fuming aqu. hydrochloric acid (few drops). Stirthe reaction mixture for 19 h at 70° C. Cool mixture to rt, removesolvent under reduced pressure and resolve the residue in EtOAc. Washthis organic layer 3 times with 5% aqu. Na₂CO₃ and extract the combinedaqueous layer 3 times with EtOAc. Wash the combined organic layers withbrine and dry with Na₂SO₄. Remove solvent under reduced pressure and drythe residue without further purification in oil pump vacuum to obtainproduct (26) as a light brown oil (2.78 g, 95%). [J. Kunes; V. Balsanek;M. Pour; V. Buchta; Collect. Czech. Chem. Commun., 2001, 66; 12;1809-1830]. ¹H NMR (400 MHz, CDCl₃): 1.26 (t, 3H, J=7.1 Hz); 3.81 (s,2H); 4.17 (q, 2H, J=7.1 Hz); 6.91-6.96 (m, 2H); 7.20 (d, 1H, J=4.8 Hz).

Step 2: (The following reaction is done in an anhydrous N₂ atmosphere.)Dissolve ester (26) (1.30 g, 7.64 mmol) in anhydrous chloroform (6.0 mL)and glacial acetic acid (6.0 mL), add N-Bromosuccinimide (1.39 g, 7.79mmol) in portions and stir the mixture for 23 h at rt. The mixture isdiluted with an equal volume of water, the organic layer separated andwashed with a 1M aqu. NaOH, water, again with 1M aqu. NaOH and water (2times). Finally wash the organic layer with brine and dry with Na₂SO₄.Remove solvent under reduced pressure. Purify crude product bypreparative radial chromatography (silica gel 60 PF, CyH/EtOAc 5+1] toobtain product (27) as an impured (according to NMR: 20% sideproduct)orange liquid (1.61 g, 85%) which is used without any furtherpurification. [P. M. Jackson; C. J. Moody; P. Sha; J. Chem. Soc. PerkinTrans. 1; 1990; 2909-2918]. ¹H NMR (400 MHz, CDCl₃): 1.26 (t, 3H, J=7.1Hz), 3.73 (s, 2H); 4.17 (q, 2H, J=7.1 Hz); 6.67 (d, 1H, J=3.5 Hz); 6.88(d, 1H, J=3.5 Hz).

Step 3: (The following reaction is done in an oxygenfree N₂ atmosphere.)Ethanol (1.47 mL), Tetrakis-(triphenylphosphine)-palladium(0) (59.0 mg,2.5 mol %) and aqu. Na₂CO₃ (1.60 g, 5.60 mmol; presolved in 2.0 mL H₂O)are subsequently added to dissolved 2-Amino-benzeneboronic acid (28)(341 mg, 2.20 mmol) in toluene (16 mL). The reaction mixture is degassed5 times and flooded with N₂ again. Add bromide (27) (498 mg, 2.00 mmol)and rinse with toluene (4.5 mL), degas again (5 times) and stir thereaction solution 21 h at 100° C. Partition the reaction solutionbetween EtOAc and brine (1+1) and extract the separated aqueous layer 3times with EtOAc. Wash combined organic layer with brine and dry withNa₂SO₄. Remove solvent under reduced pressure and purify the crudeproduct by preparative radial chromatography (silica gel 60 PF,CyH/EtOAc 6+1, later 3+1] to obtain product (29) as a light yellow solid(300 mg, 57%). [N. Miyaura; A. Suzuki; Chem. Rev.; 1995; 95; 2457]. ¹HNMR (400 MHz, CDCl₃): 1.28 (t, 3H, J=7.1 Hz); 3.82 (s, 2H); 4.19 (q, 2H,J=7.1 Hz); 6.77-6.84 (m, 2H); 6.91 (d, 1H, J=53.5 Hz); 7.04 (d, 1H,J=3.5 Hz); 7.13 (td, 1H, J=7.8 Hz, 1.3 Hz); 7.25 (d, 1H, J=7.8 Hz).

Step 4: (The following reaction is done in an anhydrous N₂ atmosphere.)Suspend EDC hydrochloride (86.3 mg, 0.45 mmol) in anhydrousdichloromethane (1.4 mL), add triethylamine (0.063 mL, 0.45 mmol) andstir for 10 min at rt. Add 2-(2,3,4-Trimethoxy-phenyl)-acetic acid (74.7mg, 0.33 mmol) and DMAP (3.7 mg, 0.03 mmol) and stir for 15 min. Addedester (29) (64.9 mg, 0.30 mmol) and stir the reaction solution 22 h atrt. Partition the reaction solution between dichloromethane and water(1+1), separate layers and extract aqu. layer with dichloromethane (3times). Wash the combined organic layer with brine and dry with Na₂SO₄.Purify crude product by preparative radial chromatography (silica gel 60PF, CyH/EtOAc 3+2) to obtain product (30) as yellow oil (118 mg, 84%).¹H NMR (400 MHz, CDCl₃): 1.29 (t, 3H, J=7.1 Hz); 3.58 (s, 2H); 3.74 (s,3H); 3.78 (s, 3H); 3.79-3.80 (m, 2H); 3.86 (s, 2H); 4.20 (q, 2H, J=7.1Hz); 6.58 (d, 1H, J=8.6 Hz); 6.59 (d, 1H, J=3.5 Hz); 6.75 (d, 1H, J=3.5Hz); 6.85 (d, 1H, J=8.6 Hz); 7.05 (t, 1H, J=7.8 Hz); 7.26 (dd, 1H, J=7.8Hz, 1.3 Hz); 7.30 (td, 1H, J=7.8 Hz, 1.3 Hz); 7.90 (br.s; 1H), 8.38 (d,1H, J=8.3 Hz).

Step 5: Dissolve ester (30) (118 mg, 0.25 mmol) in methanol (8.0 mL),add a 1M aqu. LiOH solution (1.76 mL, 1.76 mmol) and stir 20 h at rt.Remove solvent under reduced pressure und partition residue betweenCHCl₃ and 0.5M HCl (1+1). Separate the aqueous layer and extract 3 timeswith CHCl₃. Wash the combined organic layer with brine and dry withNa₂SO₄. Remove solvent under reduced pressure and dry the residuewithout further purification in oil pump vacuum to obtain crude product(31) as light brown foam (120 mg, quant.). ¹H NMR (400 MHz, CDCl₃): 3.58(s, 2H); 3.73 (s, 3H); 3.78 (s, 3H); 3.85 (s, 2H); 3.86 (s, 3H);6.58-6.61 (m, 1H); 6.59 (d, 1H, J=8.3 Hz); 6.77 (d, 1H, J=3.5 Hz); 6.86(d, 1H, J=8.3 Hz); 7.06 (t, 1H, J=7.8 Hz); 7.22-7.27 (m, 1H); 7.31 (td,1H, J=7.8 Hz, 1.3 Hz); 7.86 (br.s, 1H); 8.37 (d, 1H, J=8.3 Hz).

EXAMPLE 3(5-{2-[(2′,3′,4′-Trimethoxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-aceticacid methyl ester (37)

Step 1: (The following reaction is done in an N₂ atmosphere.) To asolution of 2,3,4-Trimethoxyphenylboronic acid (32) (1.40 g, 6.60 mmol)in toluene (15.0 mL) is added EtOH (2.0 mL), Pd(PPh₃)₄ (208 mg, 0.18mmol) and Na₂CO₃.10H₂O (4.81 g, 16.80 mmol) in water (5.2 mL). Theresulting mixture is carefully degassed (5 times alternating vacuum andflushing with N₂). A solution of Methyl-3-bromobenzoate (9) (1.29 g,6.00 mmol) in toluene (9.0 mL) is added by syringe, the resultingmixture is again carefully degassed and stirred overnight at 100° C.Partition the mixture between brine/EtOAc (1+1), separate layers,extract the aqu. layer with EtOAc (3×), wash the combined organic layerwith brine, dry with Na₂SO₄ and remove solvent. Purify crude product bypreparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) as ayellowish oil (1.07 g, 58%). ¹H NMR (400 MHz, CDCl₃): 3.66 (s, 3H); 3.89(s, 3H); 3.92 (s, 6H); 6.74 (d, 1H, J=8.6 Hz); 7.03 (d, 1H, J=8.6 Hz);7.44 (t, 1H, J=7.8 Hz); 7.70 (d, 1H, J=7.6 Hz); 7.97 (d, 1H, J=7.8 Hz);8.15 (br.s 1H).

Step 2: Dissolve 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methylester (33) (566 mg, 1.87 mmol) in MeCN (19.0 mL) at rt and add 1M aquLiOH (9.36 mL, 9.36 mmol). Stir reaction mixture overnight at rt. Quenchreaction mixture (cooling bath) with 1 M aqu. HCl (to get pH ca. 3).Extract the mixture with EtOAc (3×), wash the combined organic layerwith brine and dry with Na₂SO₄. Recrystallize crude product fromEtOAc/CyH 1+3 to obtain 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid(34) as a white solid (392 mg, 72%). ¹H NMR (400 MHz, CD₃OD: 3.68 (s,3H); 3.93 (br.s, 6H); 6.92 (d, 1H, J=8.6 Hz); 7.11 (d, 1H, J=8.6 Hz);7.54 (t, 1H, J=7.7 Hz); 7.75 (d, 1H, J=7.6 Hz); 8.01 (d, 1H, J=7.8 Hz);8.18 (br.s 1H).

Step 3: (The following reaction is done in an anhydrous N₂ atmosphere.)Dissolve 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid (34) (107 mg,0.37 mmol) in anhydrous DCM (3.0 mL) and add anhydrous DMF (3 drops,cat. amount). Then add slowly oxalyl chloride (42 μL, 0.48 mmol) bykeeping temperature at ca. 15° C. with a water bath and stir the turbidmixture for additional 2 h at rt. Transfer the formed crude solution of2′,3′,4′-Trimethoxy-biphenyl-3-carbonyl chloride (35) to an ice cooledsolution of [5-(2-Amino-phenyl)-thiophen-2-yl]-acetic acid methyl ester(36) (70 mg, 0.28 mmol) in anhydrous DCM (4.5 mL) and anhydrous pyridine(0.75 mL). Stir the reaction mixture for 3 h at rt. Pour the reactionmixture into ice cooled 1M aqu. HCl, extract with DCM (3×), wash thecombined organic layer with brine and dry with Na₂SO₄. Purify the crudeproduct by preparative radial chromatography (silica gel, EtOAc/CyH 1+3,later 1+2) to obtain(5-{2-[(2′,3′,4′-Trimethoxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-aceticacid methyl ester (37) as a brownish sticky solid (96 mg, 65%). ¹H NMR(400 MHz, CDCl₃): 3.64 (s, 3H); 3.71 (s, 3H); 3.84 (s, 2H); 3.90 (s,3H); 3.92 (s, 3H); 6.75 (d, 1H, J=8.8 Hz); 6.97 (d, 1H, J=3.5 Hz); 7.01(d, 1H, J=8.8 Hz); 7.03 (d, 1H, J=3.5 Hz); 7.16 (br.t, 1H, J=7.6 Hz);7.36-7.43 (m, 2H); 7.46 (t, 1H, J=7.7 Hz); 7.67 (Ψdd, 2H, J₁=7.6 Hz,J₂=1.5 Hz); 7.91 (br.s 1H); 8.41 (br.s 1H); 8.50 (d, 1H, J=8.6 Hz).

EXAMPLE 45-{2-Amino-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-2-methyl-furan-3-carboxylicacid (42)

Step 1: (The following reaction is done under exclusion of light.)Dissolve 2-Methyl-furan-3-carboxylic acid methyl ester (15) (2.00 mL,15.9 mmol) in chloroform (11 mL) and glacial acetic acid (11 mL) and addNBS (3.85 g, 21.6 mmol) portionwise in between a period of 75 min. Stirthe reaction suspension for additional 16 h at rt. Add water to thereaction mixture and extract the aqu. layer with DCM (2 times), wash thecombined organic layer with 2M aqu. NaOH, water and brine and dry itwith Na₂SO₄ to obtain 5-Bromo-2-methyl-furan-3-carboxylic acid methylester (16) (2.80 g, 80%) as a red brown oil. No further purification. ¹HNMR (400 MHz, CDCl₃): 2.54 (s, 3H); 3.80 (s, 3H); 6.53 (s, 1H).

Step 2: (The following reaction is done in a N₂ atmosphere.) DissolvePdCl₂(dppf).CH₂Cl₂ (245 mg, 0.30 mmol), KOAc (2.52 g, 25.7 mmol) andBis-(pinacolato)diboron (3.81 g, 15.00 mmol) in anhydrous DMSO (50 mL)and add 4-Bromo-3-nitro-phenylamine (38) (2.17 g, 10.00 mmol). Degas themixture carefully and flush with N₂ again (5 times) and stir it for 24 hat 80° C. Cool the reaction mixture to rt and partition it between waterand toluene. Extract the aqu. layer with EtOAc (3 times), wash thecombined organic layer with water and brine and dry it with Na₂SO₄. Theobtained crude residue is filtrated through a short pad of silica gelusing EtOAc/CyH (1+1) to obtain3-Nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(39) (2.04 g, 77%) as a dark red solid. No further purification. ¹H NMR(400 MHz, CDCl₃): 1.37 (s, 12H); 3.95 (br.s, 2H); 6.87 (dd, 1H, J₁=7.8Hz, J₂=2.3 Hz); 7.30 (d, 1H, J=8.1 Hz); 7.35 (d, 1H, J=2.3 Hz).

Step 3: (The following reaction is done in a N₂ atmosphere.) DissolvePd(PPh₃)₄ (59 mg, 0.05 mmol) and 5-Bromo-2-methyl-furan-3-carboxylicacid methyl ester (23) (447 mg, 2.04 mmol) in DME (3 mL) and stir for 10min at rt. Add3-Nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(39) (465 mg, 1.76 mmol) followed by an aqu. 1 M sodium bicarbonatesolution (5.10 mL, 5.10 mmol). Degas the reaction mixture carefully,flush with N₂ (5 times) and stir for 4.5 h at 90° C. (reflux). Coolreaction mixture to rt, remove organic solvent under reduced pressureand partition the residue between water and EtOAc. Extract the aqu.layer with EtOAc (3 times), wash the combined organic layer with waterand brine and dry it with Na₂SO₄. Purify the obtained crude product byflash chromatography (silica gel, EtOAc/CyH 1+3, later 1+2) to obtain5-(4-Amino-2-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester(40) (167 mg, 34%) as a red solid. ¹H NMR (400 MHz, CDCl₃): 2.57 (s,3H); 3.81 (s, 3H); 4.05 (br.s, 2H); 6.68 (s, 1H); 6.81 (dd, 1H, J₁=8.3Hz, J₂=2.3 Hz); 6.99 (d, 1H, J=2.3 Hz); 7.39 (d, 1H, J=8.3 Hz).

Step 4: (The following reaction is done in an anhydrous N₂ atmosphere.)Suspend EDC.HCl (138 mg, 0.72 mmol) and Et₃N (101 μL, 0.72) in anhydrousDCM (4.5 mL) and stir the resulting solution for 5 min at rt. Add2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8mg, 0.07 mmol) and stir the resulting solution for 10 min. Add5-(4-Amino-2-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester(40) (100 mg, 0.36 mmol) and stir the reaction solution for 22 h at rt.Quench reaction solution with sat. aqu. NH₄Cl and water, separate layersand extract aqu. layer with DCM (3 times). Wash the combined organiclayer with water and brine and dry with Na₂SO₄. Purify the crude productby preparative radial chromatography (silica gel, EtOAc/CyH 1+1) toobtain2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylicacid methyl ester (41) (96 mg, 55%) as an yellow solid. ¹H NMR (400 MHz,CDCl₃): 2.55 (s, 3H); 3.65 (s, 2H); 3.79 (s, 3H); 3.81 (s, 6H); 3.82 (s,3H); 6.50 (s, 2H); 6.77 (s, 1H); 7.53 (d, 1H, J=8.6 Hz); 7.66 (dd, 1H,J=8.6 Hz, J₂=2.0 Hz); 7.93 (br.s, 1H); 7.96 (d, 1H, J=2.0 Hz).

Step 5: Dissolve2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylicacid methyl ester (41) (50 mg, 0.10 mmol) in THF (11.0 mL) and MeOH (0.5mL) at rt and add 1M aqu LiOH (525 μL, 0.52 mmol). Stir the reactionmixture for 17 h at rt. Add dropwise 1M aqu. HCl (580 μL, 0.58 mmol) andextract the mixture with EtOAc (3 times), wash the combined organiclayer with brine and dry it with Na₂SO₄. Purify the obtained crudeproduct by preparative TLC (silica gel, EtOAc/MeOH 9+1) to obtain2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylicacid (42) (35 mg, 71%) as a brown sticky solid. ¹H NMR (400 MHz, CDCl₃):2.61 (s, 3H); 3.70 (s, 2H); 3.86 (s, 3H); 3.87 (s, 6H); 6.51 (s, 2H);6.85 (s, 1H); 7.29 (br.s, 1H); 7.58 (d, 1H, J=8.6 Hz); 7.62 (dd, 1H,J₁=9.0 Hz, J₂=2.2 Hz); 7.98 (d, 1H, J=2.0 Hz).

EXAMPLE 5 {4-[2-(3,4,5-Trimethoxy-phenyl)-acetyl]-piperazin-1-yl}-aceticacid ethyl ester (44)

(The following reaction is done in an anhydrous N₂ atmosphere.) SuspendEDC.HCl (188 mg, 0.98 mmol) and Et₃N (137 μL, 0.98 mmol) in anhydrousDCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8mg, 0.07 mmol) and stir the resulting solution for 10 min. Add1-(Ethoxycarbonylmethyl)piperazine (43) (112 mg, 0.65 mmol) and stir thereaction solution overnight at rt. Quench reaction solution with sat.aqu. NH₄Cl and water, separate layers and extract aqu. layer with DCM (3times). Wash the combined organic layer with water and brine and drywith Na₂SO₄. Purify the crude product by preparative radialchromatography (silica gel, EtOAc/MeOH 10+1) to obtain{4-[2-(3,4,5-Trimethoxy-phenyl)-acetyl]-piperazin-1-yl}-acetic acidethyl ester (44) (99 mg, 40%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃): 1.25 (t, 3H, J=7.1 Hz); 2.48 (br.m, 2H); 2.58 (br.m, 2H); 3.21(br.s, 2H); 3.53 (br.m, 2H); 3.65 (s, 2H); 3.71 (br.m, 2H); 3.81 (s,3H); 3.82 (s, 6H); 4.16 (q, 2H, J=7.1 Hz); 6.42 (s, 2H).

EXAMPLE 6{4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid(46)

Step 1: (The following reaction is done in an anhydrous N₂ atmosphere.)Suspend EDC.HCl (376 mg, 1.96 mmol) and Et₃N (275 μL, 1.96 mmol) inanhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt.Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (346 mg, 1.44 mmol) andDMAP (17 mg, 0.14 mmol) and stir the resulting solution for 15 min. Add1-(Ethoxycarbonylmethyl)piperazine (43) (224 mg, 1.30 mmol) and stir thereaction solution overnight at rt. Quench reaction solution with water,separate layers and extract aqu. layer with EtOAc (3 times). Filtratethe combined organic layer through a short pad of silica gel and removesolvent. Purify the crude product by preparative radial chromatography(silica gel, EtOAc/MeOH 9+1) to obtain{4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acidethyl ester (45) (426 mg, 83%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃): 1.26 (t, 3H, J=7.1 Hz); 2.45-2.70 (br.m, 6H); 2.89 (t, 2H, J=7.7Hz); 3.26 (br.s, 2H); 3.43-3.56 (br.m, 2H); 3.61-3.76 (br.m, 2H); 3.80(s, 3H); 3.83 (s, 6H); 4.18 (q, 2H, J=7.1 Hz); 6.41 (s, 2H).

Step 2: Dissolve{4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acidethyl ester (45) (100 mg, 0.25 mmol) in MeOH (2.0 mL) at rt and add 2Maqu NaOH (260 μL, 0.52 mmol). Stir the reaction mixture for 1 h underreflux. Add dropwise 1M aqu. HCl (550 μL, 0.55 mmol), extract themixture with EtOAc (3 times) and remove solvent obtain{4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid(46) (88 mg, 95%) as a brown sticky solid. No further purification. ¹HNMR (400 MHz, CDCl₃/CD₃OD 9+1): 2.54 (br.t, 2H); 2.78 (t, 2H, J=7.5 Hz);2.83-3.10 (br.m, 2H); 3.24 (s, 2H); 3.43-3.62 (br.m, 2H); 3.68 (s, 3H);3.73 (s, 6H); 3.74-3.85 (br.m, 4H); 6.34 (s, 2H).

EXAMPLE 7{2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-aceticacid methyl ester (50)

Step 1: (The following reaction is done in an oxygenfree N₂ atmosphere.)Add ethanol (0.8 mL), Tetrakis-(triphenylphosphine)-palladium(0) (30 mg,2.2 mol %) and Na₂CO₃ decahydrate (944 mg, 3.30 mmol; presolved in 1.2mL H₂O) subsequently to dissolved 2-Amino-benzeneboronic acid (48) (201mg, 1.30 mmol) in toluene (6.0 mL). Degas the reaction mixture for 5times and flood with N₂ again. Add (3-Bromo-phenyl)-acetic acid methylester (47) (270 mg, 1.18 mmol) in toluene (6.0 mL), degas again (5times) and stir the reaction solution overnight at 100° C. Partition thereaction solution between EtOAc and brine (1+1) and extract theseparated aqueous layer 3 times with EtOAc. Wash combined organic layerwith brine and dry with Na₂SO₄. Remove solvent under reduced pressureand purify the crude product by preparative radial chromatography(silica gel 60 PF, CyH/EtOAc 3+1) to obtain(2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (49) as an orange oil(304 mg, 81%). ¹H NMR (400 MHz, CDCl₃): 3.66 (s, 2H); 3.69 (s, 3H);3.62-3.86 (br.s, 2H); 6.75 (d, 1H, J=8.1 Hz); 6.80 (t, 1H, J=7.3 Hz);7.11 (d, 1H, J=7.3 Hz); 7.15 (d, 1H, J=8.1 Hz); 7.22-7.26 (br.m, 1H);7.32-7.42 (m, 3H).

Step 2: (The following reaction is done in an anhydrous N₂ atmosphere.)Suspend EDC.HCl (61 mg, 0.32 mmol) and Et₃N (44 μL, 0.32 mmol) inanhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt.Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (55 mg, 0.23 mmol) andDMAP (2 mg, 0.02 mmol) and stir the resulting solution for 15 min. Add(2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (49) (50 mg, 0.21mmol) and stir the reaction solution overnight at rt. Quench reactionsolution with water, separate layers and extract aqu. layer with DCM (3times). Wash combined organic layer with brine and dry with Na₂SO₄.Purify the crude product by preparative radial chromatography (silicagel, EtOAc/CyH 1+1) to obtain{2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-aceticacid methyl ester (50) (46 mg, 48%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): 2.50 (t, 2H, J=7.6 Hz); 2.90 (t, 2H, J=7.7 Hz); 3.64 (s, 2H);3.65 (s, 3H); 3.77 (s, 6H); 3.78 (s, 3H); 6.38 (s, 2H); 7.09-7.18 (m,3H); 7.19-7.28 (m, 3H); 7.34 (d, 1H, J=8.1 Hz); 7.38 (d, 1H, J=7.8 Hz);8.31 (br.d, 1H, J=7.8 Hz).

EXAMPLE 8 4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acidmethyl ester (52)

(The following reaction is done in an anhydrous N₂ atmosphere.) SuspendEDC.HCl (80 mg, 0.41 mmol) and Et₃N (58 μL, 0.41 mmol) in anhydrous DCM(2.0 mL) and stir the resulting solution for 5 min at rt. Add3-(3,4,5-Trimethoxy-phenyl)-propionic acid (70 mg, 0.29 mmol) and DMAP(5 mg, 0.04 mmol) and stir the resulting solution for 10 min. Add4-Amino-benzoic acid methyl ester (51) (42 mg, 0.27 mmol) and stir thereaction solution 2d at rt. Quench reaction solution with water,separate layers and extract aqu. layer with DCM (3 times). Wash combinedorganic layer with brine, dry with Na₂SO₄ and filtrate it through ashort pad of silica gel using EtOAc to obtain4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acid methyl ester(52) (91 mg, 88%) as a white solid. No further purification. ¹H NMR (400MHz, CDCl₃): 2.60 (t, 2H, J=7.6 Hz); 2.91 (t, 2H, J=7.6 Hz); 3.70 (s,6H); 3.76 (s, 3H); 3.83 (s, 3H); 6.35 (s, 2H); 7.55 (d, 2H, J=8.3 Hz);7.91 (d, 2H, J=8.6 Hz); 8.09 (s, 1H).

EXAMPLE 9(5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-aceticacid (59)

Step 1: (The following reaction is done in an N₂ atmosphere.) To asolution of Methyl-2-bromobenzoate (53) (922 mg, 4.29 mmol) in toluene(11 mL) is added Pd(PPh₃)₄ (297 mg, 0.26 mmol) and Na₂CO₃.10H₂O (3.43 g,12.00 mmol) in water (3.8 mL). Degas the resulting mixture is carefully(5 times alternating vacuum and flushing with N₂). Add a solution of3,4,5-Trimethoxyphenylboronic acid (54) (1.00 g, 4.72 mmol) in toluene(10 mL) by syringe, degas the resulting mixture again carefully and stirthe resulting mixture overnight at 100° C. Partition the mixture betweenbrine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc(3×), wash the combined organic layer with brine and dry with Na₂SO₄.Purify the crude product by flash chromatography (silica gel, EtOAc/CyH1+7, later 1+5) to obtain 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acidmethyl ester (55) as a yellow solid (1.30 g, 99%). ¹H NMR (400 MHz,CDCl₃): 3.65 (s, 3H); 3.84 (s, 6H); 3.87 (s, 3H); 6.52 (s, 2H);7.35-7.42 (m, 2H); 7.50 (t, 1H, J=8.0 Hz); 7.73 (d, 1H, J=8.0 Hz).

Step 2: Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid methylester (55) (626 mg, 2.08 mmol) in MeOH (14 mL) at rt and add 1M aqu LiOH(4.2 mL, 4.20 mmol). Stir reaction mixture for 8 h under reflux. Removesolvent and partition the residue between 1 M aqu. HCl and EtOAc,separate layers, extract the aqu. layer with EtOAc (3×), wash thecombined organic layer with brine and dry with Na₂SO₄. Remove solventand recrystallize residue from EtOAc/CyH 1+2 to obtain3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (56) as a white solid(423 mg, 79%). ¹H NMR (400 MHz, CD₃OD: 3.84 (s, 3H); 3.89 (s, 6H); 6.68(s, 2H); 7.42-7.49 (m, 2H); 7.57 (t, 1H, J=7.5 Hz); 7.76 (d, 1H, J=8.0Hz).

Step 3: (The following reaction is done in an anhydrous N₂ atmosphere.)Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (56) (54 mg,0.18 mmol) in anhydrous DCM (1.3 mL) and add anhydrous DMF (1 drop, cat.amount). Then add slowly oxalyl chloride (21 μL, 0.24 mmol) by keepingtemperature at ca. 20° C. with a water bath and stir the turbid mixturefor additional 2 h at rt. Remove solvent and dry in vacuum to obtaincrude 3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl chloride (57) as a yellowsolid. No further purification.

Step 4: Add a solution of 3′,4′,5′-Trimethoxy-biphenyl-2-carbonylchloride (57) (0.18 mmol) in DCM (11.0 mL) to an ice cooled solution of[5-(2-Amino-phenyl)-thiophen-2-yl]-acetic acid methyl ester (36) (46 mg,0.18 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (0.5 mL).Stir the reaction mixture for 1 h at 0° C. and additional 20 h at rt.Pour the reaction mixture into ice cooled 1 M aqu. HCl, extract withEtOAc (2×) and DCM (2×), wash the combined organic layer with brine anddry with Na₂SO₄. Purify the crude product by preparative radialchromatography (silica gel, EtOAc/CyH 1+2) to obtain(5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-aceticacid methyl ester (58) as a light brown solid (58 mg, 59%). ¹H NMR (400MHz, CDCl₃): 3.70 (s, 3H); 3.76 (s, 6H); 3.78 (s, 2H); 3.80 (s, 3H);6.29 (d, 1H, J=3.4 Hz); 6.60 (s, 2H); 6.75 (d, 1H, J=3.4 Hz); 7.07 (t,1H, J=7.6 Hz); 7.23 (d, 1H, J=7.6 Hz); 7.31 (t, 1H, J=8.0 Hz); 7.37-7.43(m, 2H); 7.48 (t, 1H, J=7.6 Hz); 7.52 (s, 1H); 7.69 (d, 1H, J=8.0 Hz);8.45 (d, 1H, J=8.0 Hz).

Step 5: Dissolve(5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-aceticacid methyl ester (58) (56 mg, 0.11 mmol) in MeCN (3.8 mL) at rt and add1M aqu LiOH (760 μL, 0.76 mmol). Stir reaction mixture 18 h at rt.Quench reaction mixture (cooling bath) with 2M aqu. HCl. Extract themixture with EtOAc (3×), wash the combined organic layer with brine anddry with Na₂SO₄ to obtain(5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-aceticacid (59) (55 mg, 99%) as a brown solid. ¹H NMR (400 MHz, CDCl₃): 3.76(s, 6H), 3.80 (s, 3H); 3.83 (s, 2H); 6.32 (d, 1H, J=3.5 Hz); 6.60 (s,2H); 6.78 (d, 1H, J=3.5 Hz); 7.07 (t, 1H, J=7.6 Hz); 7.23 (d, 1H, J=7,6Hz); 7.32 (t, 1H, J=7.6 Hz); 7.36-7.54 (m, 3H); 7.69 (d, 1H, J=8.0 Hz);8.43 (d, 1H, J=8.0 Hz).

EXAMPLE 10 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid{2-[5-(1H-tetrazol-5-ylmethyl)-thiophen-2-yl]-phenyl}-amide (87)

Step 1: (The following reaction is done in an anhydrous N₂ atmosphere.)Dissolve nitrile (82) (500 mg, 4.06 mmol) in anhydrous DMF (2.7 mL),cool to 0° C., add N-bromosuccinimide (795 mg, 7.79 mmol) in portionsover a period of 20 min and stir the mixture for 22 h at rt. Partitionthe reaction solution between dichloromethane and water (1+1) andextract the separated aqueous layer 2 times with dichloromethane. Washcombined organic layer with water and brine and dry with Na₂SO₄. Removesolvent under reduced pressure and purify the crude product bypreparative radial chromatography (silica gel 60 PF, CyH/EtOAc 10+1] toobtain (5-bromo-thiophen-2-yl)-acetonitrile (83) as a light yellowliquid (745 mg, 91%). [M. A. Ismail, R. Brun, J. D. Easterbrook, F. A.Tanious, W. D. Wilson, D. W. Boykin, J. Med. Chem. 2003; 46 (22);4761-4769]. ¹H NMR (400 MHz, CDCl₃): 3.81 (d, 2H, J=1.0 Hz); 6.81 (d,1H, J₁=3.8 Hz, J₂=1.0 Hz); 6.92 (d, 1H, J=3.8 Hz).

Step 2: (The following reaction is done in an oxygenfree N₂ atmosphere.)Dissolve tetrakis-(triphenylphosphine)-palladium(0) (29 mg, 2.5 mol %)and nitrile (83) (101 mg, 0.50 mmol) in DME (3.7 mL). The reactionmixture is degassed 5 times and flooded with N₂ again. Add2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (84) (120mg, 0.55 mmol), rinse with DME (0.5 mL), add aqu. 1M NaHCO₃, degas again(5 times) and stir the reaction solution 2 h at 90° C. (reflux). Aftercooling to rt partition the reaction mixture between EtOAc and brine(1+1) and extract the separated aqueous layer 3 times with EtOAc. Washcombined organic layer with brine and dry with Na₂SO₄. Remove solventunder reduced pressure and purify the crude product by preparativeradial chromatography (silica gel 60 PF, CyH/EtOAc 2+1) to obtain[5-(2-amino-phenyl)-thiophen-2-yl]-acetonitrile (85) as a brownish oil(84 mg, 78%). ¹H NMR (400 MHz, CDCl₃): 3.89 (br.s, 2H); 5.20-6.50 (br.s,2H); 6.92 (t, 1H; J=7.6 Hz); 6.95-7.00 (m, 1H); 6.99 (d, 1H; J=3.8 Hz);7.11 (d, 1H; J=3.8 Hz); 7.21 (dd, 1H; J₁=7.6 Hz, J₂=1.3 Hz); 7.27 (dd,1H; J₁=7.6 Hz, J₂=1.3 Hz).

Step 3: (The following reaction is done in an anhydrous N₂ atmosphere.)Add a solution of 2′,3′,4′-trimethoxy-biphenyl-3-carbonyl chloride (35)(117 mg, 0.38 mmol) in dichloromethane (1.3 mL) to an ice cooledsolution of the aniline (85) (82 mg, 0.38 mmol) in anhydrousdichloromethane (2.6 mL) and anhydrous pyridine (0.65 mL). Stir thereaction mixture for 1 h at 0° C. and additional 21 h at rt. Pour thereaction mixture into ice cooled 1M aqu. HCl (20 mL), extract withdichloromethane (2×) and EtOAc (1×), wash the combined organic layerwith brine and dry with Na₂SO₄. Purify the crude product by preparativeradial chromatography (silica gel 60 PF, EtOAc/CyH 1+3 (incl. 2% MeOH),later 1+3) to obtain anilide (86) as an orange solid (132 mg, 71%). ¹HNMR (400 MHz, C₆D₆) 2.88 (d, 2H, J=1.0 Hz); 3.53 (s, 3H); 3.55 (s, 3H),3.94 (s, 3H), 6.63 (d, 1H, J=3.5 Hz); 6.64 (d, 1H, J=8.6 Hz); 6.66 (d,1H, J=3.5 Hz); 6.99 (td, 1H; J₁=7.6 Hz, J₂=1.0 Hz); 7.01 (d, 1H,_(J)=8.6 Hz), 7.25-7.34 (m, 3H); 7.74 (dt, 1H; J₁=7.8 Hz, J₂=1.5 Hz);7.97 (dt, 1H, J₁=7.8 Hz, J₂=1.5 Hz), 8.18 (t, 1H, J=1.5 Hz), 8.34 (br.s, 1H); 9.14 (d, 1H, J=7.8 Hz).

Step 4: (The following reaction is done in an anhydrous N₂ atmosphere.)Dissolve anilide (86) (60 mg, 0.12 mmol) in anhydrous DMF (2.0 mL), addsodium azide (18 mg, 0.14 mmol) and ammonium chloride (9 mg, 0.85 mmol)and stir the reaction solution for 2d at 90° C. Add again sodium azide(18 mg, 0.14 mmol) and ammonium chloride (9 mg, 0.85 mmol) and stir foradditional 3d at 90° C. Cool mixture to rt and adjust pH=1 by additionof 1M HCl. Extract aqueous layer with dichloromethane (3×). Wash thecombined organic layer with brine, dry with Na₂SO₄ and remove solventunder reduced pressure. Purify the crude product by preparative radialchromatography (silica gel, EtOAc/CyH 1+2, later EtOAc/MeOH 9+1) toobtain 2′,3′,4′-trimethoxy-biphenyl-3-carboxylic acid{2-[5-(1H-tetrazol-5-ylmethyl)-thiophen-2-yl]-phenyl}-amide (87) as ayellow solid (50 mg, 76%) [F. Osterod, L. Peters, A. Kraft, T. Sano, J.J. Morisson, N. Feeder, A. B. Holmes, J. Mater. Chem. 2001, 11,1625-1633 and refer. therein. ¹H-NMR (400 MHz, (CD₃)₂SO): 3.61 (s, 3H);3.80 (s, 3H); 3.84 (s, 3H); 4.45 (s, 2H); 6.93 (d, 1H; J=8.6 Hz); 6.93(d, 1H; J=3.5 Hz); 7.11 (d, 1H, J=8.6 Hz); 7.26 (d, 1H, J=3.5 Hz); 7.33(td, 1H, J₁=7.3 Hz, J₂=1.8 Hz); 7.35 (td, 1H, J₁=7.3 Hz, J₂=1.8 Hz);7.43-7.47 (m, 1H); 7.53 (t, 1H, J=7.7 Hz); 7.61 (dd, 1H, J₁=7.0 Hz,J₂=2.0 Hz); 7.66 (d, 1H, J=7.6 Hz); 7.85 (d, 1H, J=7.6 Hz); 7.99 (s,1H); 10.07 (s, 1H).

EXAMPLE 11 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid(2-bromo-5-nitro-phenyl)-amide (89)

(The following reaction is done in an anhydrous N₂ atmosphere.) Add asolution of 2′,3′,4′-trimethoxy-biphenyl-3-carbonyl chloride (35) (345mg, 1.13 mmol) in dichloromethane (5 mL) to an ice cooled solution of2-bromo-5-nitro-phenylamine (88) (232 mg, 1.07 mmol) in anhydrousdichloromethane (12 mL) and anhydrous pyridine (2.9 mL). Stir thereaction mixture for 15 min at 0° C. and additional 17 h at rt. Pour thereaction mixture into ice cooled 1M aqu. HCl (to get pH ca. 3), extractwith EtOAc (3×), wash the combined organic layer with brine and dry itwith Na₂SO₄ to afford crude 2′,3′,4′-trimethoxy-biphenyl-3-carboxylicacid (2-bromo-5-nitro-phenyl)-amide (89) as a beige solid (542 mg,quant.). ¹H NMR (400 MHz, CDCl₃): 3.72 (s, 3H); 3.91 (s, 3H); 3.93 (s,3H); 6.77 (d, 1H, J=8.6 Hz); 7.08 (d, 1H, J=8.6 Hz); 7.56 (t, 1H, J=8.8Hz); 7.75 (d, 2H, J=8.8 Hz); 7.86 (d, 1H, J=8.8 Hz), 7.87 (d, 1H, J=8.8Hz); 8.09 (t, 1H, J=1.7 Hz); 8.61 (br. s, 1H); 9.59 (d, 1H, J=2.5 Hz).

EXAMPLE 12 N-(3-Nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(91)

(The following reaction is done in an anhydrous N₂ atmosphere.) SuspendEDC hydrochloride (402 mg, 2.10 mmol) and Et₃N (293 μL, 2.10 mmol) inanhydrous dichloromethane (17.0 mL) and stir the resulting solution for5 min at rt. Add 3-(3,4,5-trimethoxy-phenyl)-propionic acid (481 mg,2.00 mmol) and DMAP (24 mg, 0.20 mmol) and stir the resulting solutionfor 5 min. Add 3-nitro-phenylamine (90) (414 mg, 3.00 mmol) and stir thereaction solution 24 h at rt. Quench reaction solution with sat. aqu.NH₄Cl and water, separate layers and extract aqu. layer with EtOAc (3times). Wash the combined organic layer with water and brine and drywith Na₂SO₄. Purify the crude product by preparative radialchromatography (silica gel 60 PF, EtOAc/CyH 1+1) to obtainN-(3-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide (91) (508mg, 70%) as a yellowish solid. ¹H NMR (400 MHz, CDCl₃): 2.65 (t, 2H,J=7.3 Hz); 2.98 (t, 2H, J=7.3 Hz); 3.79 (s, 6H); 3.81 (s, 3H), 6.42 (s,2H); 7.41 (s, 1H); 7.45 (t, 1H, J=8.0 Hz); 7.84 (d, 1H, J=8.0 Hz); 7.92(d, 1H, J=8.0 Hz); 8.31 (s, 1H).

The compounds referred to in the following SCHEME 16 are those compoundsreferred to as the particularly preferred compounds herein.

Sialyl Lewis^(X) Tyrosine Sulfate Assay (sLe^(x) TSA):

Compounds of the present invention are assayed on a molecular level fortheir ability to inhibit the binding of P-, L-, or E-selectin chimericmolecules to sLe^(x) and tyrosinesulfate residues linked to a polymericmatrix as a PSGL-1 substitute. IC₅₀-values are determined.

Microtiter plates are coated overnight in carbonate buffer pH9.6 withgoat anti human Fc mAB (10 μg/ml). After washing in assay buffer (25 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 150 mM NaCl,1 mM CaCl₂ pH7.4) and blocking (3% bovine serum albumin (BSA) in assaybuffer) plates are incubated for 2 h at 37° C. with humanP-Selectin-IgG-chimera (0.61 nM respectively 150 ng/mL) or humanL-Selectin-IgG-chimera (0.61 nM respectively 89 ng/mL) or humanE-Selectin-IgG-chimera (0.61 nM respectively 131 ng/mL). 5 μl ofsLe^(x)-tyrosine sulfate polyacrylamide (1 mg/ml) carrying 15% sLe^(x),10% Tyrosine-sulfate and 5% biotin is complexed with 20 μlStreptavidin-Peroxidase solution (1 mg/ml) and 25 μl assay bufferwithout CaCl₂. For use in the assay, the ligand complex is diluted1:10000 in assay buffer and further diluted 1:1 with varying amounts ofcompounds in assay buffer incl. 2% DMSO. This mixture is added to thewells precoated with E- or P-selectin. After incubation for 2 h at 37°C., wells are washed for six times with in assay buffer incl. 0.005%Polyoxyethylenesorbitan monolaurate (TWEEN 20), developed for 10-15 minwith 20 μl 3,3′,5,5′-tetramethylbenzidine (TMB)/H₂0₂ substrate solutionand stopped with 20 μl 1 M H₂SO₄. Bound sLe^(x)-Tyrosine sulfate ligandcomplex is determined by measuring optical density at 450 nm vs. 620 nmin a Fusion alpha-FP reader (sold from Packard Bioscience, Dreieich,Germany).

Results from sLe^(x)TSA: IC₅₀ Data for E-/P-/L-Selectin

IC₅₀ IC₅₀ IC₅₀ Compound E-Selectin [μM] P-Selectin [μM] L-Selectin [μM]Bimosiamose >500 95.0 >500 60 18.2 15.0 12.8 61 >500 186.1 385.3 62 74.746.4 45.3 63 >500 28.5 76.1 64 >500 107.1 382.9Results from sLe^(x)TSA: IC₅₀ Data for E-/P-/L-Selectin

IC₅₀ IC₅₀ IC₅₀ Compound E-Selectin [μM] P-Selectin [μM] L-Selectin [μM]87 — 32.6 59.5Flow Chamber Assay/Cell Adhesion and Rolling under Flow Conditions

To assess the capability of compounds to inhibit cell binding underdynamic conditions resembling the flow in a blood vessel, flow chamberassays addressing/testing binding of HL-60 cells/various cell lines toP-selectin, L-selectin and E-selectin chimeric molecules are performed.

Cell attachment under flow conditions are determined using a parallelflow chamber system. A 35 mm polystyrene culture dish is coated for 1hour at room temperature with coating buffer (50 mMtris-(hydroxymethyl)aminomethane buffer (Tris), 150 mM NaCl, 2 mM CaCl₂;pH 7.4) containing human E- or P-selectin-IgG chimera at concentrationsof 2.5 μg/ml or 10 μg/ml, respectively. After removal of the coatingsolution non specific binding sites are blocked for an additional hourwith 1% BSA in coating buffer at room temperature. After washing withassay buffer (“Roswell Park Memorial Institute 1640” (RPMI 1640)+10 mMHEPES) the dish is fitted into a parallel plate laminar flow chamber(sold from Glycotech, Rockville, Md.) and mounted on an invertedphase-contrast microscope (sold from Olympus, Hamburg, Germany) equippedwith a CCD camera (JVC) that is connected to a PC. Employing aperistaltic pump (sold from Ismatec, Wertheim-Mondfeld, Germany) there-circulating system is equilibrated with assay buffer containing 125μM compound or vehicle control (DMSO). Cells (1 million/ml) are added tothe chamber and allowed to distribute for 2 minutes at a high flow rate.The flow rate is then decreased resulting in a calculated flow shear of1 dyne/cm². Video sequences of 10 low power fields are digitallyrecorded after 5 minutes continuous flow. The percentage of modulationis calculated from the mean number of cells per field that attached tothe coated dish surface in the presence versus absence of compound of atindependent experiments.

Data from Flow Chamber Assay for E- and P-Selectin

Values are given as normalized ratios of %-inhibition of compound xdivided by %-inhibition of bimosiamose.

MJ

E-Selectin P-Selectin Compound [Ratio] [Ratio] 63 1.46 1.06 64 1.27 1.0187 1.23 2.62

1. Pharmaceutical compositions comprising at least one compound of theformulas (Ia) or (Ib) and a pharmaceutically acceptable carrier which isuseful in a medicine,

wherein the symbols, indices and substituents have the following meaning—X—=

with m=0,1; n=an integer from 1 to 3

wherein “ring” is

and with R¹ being H, NO₂, CF₃, F, Cl, Br, I, CN, CH₃, NH₂, NHAlkyl,NHAryl, NHAcyl and k=0,1

T being O, S or [H,H]; p=0,1,2, —Y=

with s being 0 or 1, R² being CO₂H, CO₂Alkyl, CO₂Aryl, CO₂NH₂,CO₂Aralkyl, SO₃H, SO₂NH₂, PO(OH)₂, 1-H-tetrazolyl-, CHO, COCH₃, CH₂OH,NH₂, NHAlkyl, N(Alkyl)Alkyl′, OCH₃, CH₂OCH₃, SH, F, Cl, Br, I, CH₃,CH₂CH₃, CN, CF₃ R³ independently from R² being H, CH₃, CH₂CH₃, CF₃, F,Cl, Br, I, CN, NO₂ and R⁴ independently from R² and R³ being H, CH₃,CH₂CH₃, CF₃, F, Cl, Br, I, CN, NO₂, R² R⁵ being H, NO₂, CF₃, F, Cl. Br,I, CN, CH₃, OCH₃, SH, NH₂ and —W—=—(CH₂—)_(v), cis-CH═CH— ortrans-CH═CH—, and v being 0,1,2; in case that —W— is cis-CH═CH— ortrans-CH═CH—, R² must not be NH₂ or SH;

with t being 0,1,2 —Z=

R⁷ independently from R² being H, NO₂, CF₃, F, Cl. Br, I, CN, CH₃, OCH₃,SH, NH₂,

with K=NH, NMe, O, S or the pharmaceutically acceptable salts, esters oramides and prodrugs of the above identified compounds of formulas (Ia)or (Ib).
 2. Pharmaceutical compositions according to claim 1, whereinthe compounds are defined by formulas (IIa) or (IIb)

wherein —Y is as defined as in claim 1 and —X′— is X (b) or X (c). 3.Pharmaceutical compositions according to claim 1, wherein the compoundsare defined by formulas (A1), (B1), (A2) or (B2)

wherein —X′— and —Y are as defined in claim 2 and wherein —X″— is

and wherein —Y′ is

wherein all indices, symbols and substituents are as defined above. 4.Pharmaceutical compositions according to claim 3, wherein the compoundsare defined by formulas (C) or (D)

wherein —X″— and —Y′ are as defined in claim
 3. 5. Pharmaceuticalcompositions according to claim 4, wherein the compounds are defined byformulas (E) or (F)

wherein —X″— is as defined in claim 3 and —Y″ is

with R⁹ being CO₂H, CO₂alkyl, CO₂aryl, CO₂NH₂, CO₂aralkyl, CH₂SO₃H,CH₂SO₂NH₂, CH₂PO(OH)₂, 1-H-tetrazolyl, CHO, COCH₃, CH₂OH, CH₂NH₂,CH₂NHalkyl, CH₂N(alkyl)alkyl′, CH₂OCH₃, CH₂SH, wherein all indices,symbols and substituents are as defined in claim
 1. 6. Chemicalcompounds having the general structure of formula (C) or (D) or (E) or(F) according to claim 4 or
 5. 7. Use of compounds having the structureof formulas (Ia) or (Ib) as defined in claim 1 for the preparation of amedicine for the treatment of Chronic Obstructive Pulmonary Disease(COPD), acute lung injury (ALI), cardiopulmonary bypass, acuterespiratory distress syndrome (ARDS), Crohn's disease, septic shock,sepsis, chronic inflammatory diseases such as psoriasis, atopicdermatitis, and rheumatoid arthritis, and reperfusion injury that occursfollowing heart attacks, strokes, atherosclerosis, and organtransplants, traumatic shock, multi-organ failure, autoimmune diseaseslike multiple sclerosis, percutaneous transluminal angioplasty, asthmaand inflammatory bowel disease.
 8. Use of compounds having the structureof formulas (C) or (D) as defined in claim 4 for the preparation of amedicine for the treatment of Chronic Obstructive Pulmonary Disease(COPD), acute lung injury (ALI), cardiopulmonary bypass, acuterespiratory distress syndrome (ARDS), Crohn's disease, septic shock,sepsis, chronic inflammatory diseases such as psoriasis, atopicdermatitis, and rheumatoid arthritis, and reperfusion injury that occursfollowing heart attacks, strokes, atherosclerosis, and organtransplants, traumatic shock, multi-organ failure, autoimmune diseaseslike multiple sclerosis, percutaneous transluminal angioplasty, asthmaand inflammatory bowel disease.
 9. Use of compounds having the structureof formulas (Ia) or (Ib) as defined in claim 1 for the preparation of amedicine for the treatment, diagnosis or prophylaxis of inflammatorydisorders.
 10. Use of compounds having the structure of formulas (Ia) or(Ib) as defined in claim 1 for the preparation of a vehicle for drugtargeting of diagnostics or therapeutics.
 11. Use of compounds havingthe structure of formulas (Ia) or (Ib) as defined in claim 1 for thepreparation of a cosmetic or dermatological composition.
 12. Cosmeticcompositions comprising at least one compound of the formulas (Ia) or(Ib) as in claim 1 and at least one cosmetically tolerable component.13. Dermatological compositions comprising at least one compound offormulas (Ia) or (Ib) as in claim 1 and at least one dermatologicallytolerable component.